Glycolytic impairment - what are the practical implications?

[Andy]

So there is some evidence for impairment of glycolysis in pwME, leading to use of other fuel sources. I'm curious as to what the practical implications of this impairment on glucose itself (if anybody knows).

If glycolysis is impaired, does it meant that glucose is used up at the same rate as normal and the output of that process is less, or does it mean that the throughput of that process is lessened?

Additionally, if other fuel is used to make up for the lack of supply from glycolysis, would this then mean that less glucose is used than normal?

And if less glucose is being used for fuel then would that then lead to higher concentrations of glucose than normal somewhere in the system? If so, what would the implications of that be?

I have no answers myself, but it seems to be an interesting area to look at in my opinion.

@Simon M , any thoughts?

 

[Trish]

From my limited knowedge.

Glucose is the breakdown product of sugars and starches. The amount in the blood is regulated by insulin released from the pancreas that moves the glucose from the blood into cells when they need it, and any excess is stored in the liver as glycogen or converted to fat. So circulating levels of glucose should be kept within a safe range unless someone is diabetic.

Glucose is partially broken down in the cytoplasm of cells by glycolysis which produces a small amount of energy as ATP, and pyruvate. This is called anaerobic respiration because it doesn't use oxygen.

The pyruvate is then further broken down inside the mitochondria in a series of steps called the citric acid cycle to produce a lot more ATP. This is the process that uses oxygen and releases carbon dioxide.

There is some suggestion that in ME there is a problem with pyruvate dehydrogenase that partially prevents the use of pyruvate in the citric acid cycle, and/or a problem with the complexes in the mitochondria that are involved in the series of stages of breakdown and energy production.

The mitocondrial process can use alternative sources of energy from proteins and fats.

If the breakdown of glucose process is incomplete and the cells use alternative energy sources, presumably more of the glucose produced from food will end up being stored as fat or glycogen which can then be used for energy production later.

Some people suggest the keto diet is helpful for ME because it is very low in carbs, so forces the cells to use fats as the main energy source.

That's as far as my knowledge takes me. I'm sure others can correct my errors and add more detail.

 

[Trish]

Here are a couple of posts relevant to this:
https://www.s4me.info/threads/cellu...-with-chronic-fatigue-syndrome.257/#post-6871

https://www.s4me.info/threads/subst...-in-patients-with-cfs-tomas-et-al-2020.17464/

 

[Andy]

presumably more of the glucose produced from food will end up being stored as fat or glycogen which can then be used for energy production later.

Thanks Trish. I think that my underlying question, which is based on several what-ifs, is "if glycolysis is impaired such that we have an excess of 'free' glucose AND if the normal mechanisms for dealing with that excess glucose is impaired in some way, what would be the result?". I'm more thinking aloud than anything else, in the hope that someone will have some insight.

 

[Wonko]

A pwME will put on more fat if eating 5kg of cake a week than someone who doesn't have ME, even with exactly the same activity levels?

 

[Trish]

So there is some evidence for impairment of glycolysis in pwME, leading to use of other fuel sources.

I think that my underlying question, which is based on several what-ifs, is "if glycolysis is impaired such that we have an excess of 'free' glucose AND if the normal mechanisms for dealing with that excess glucose is impaired in some way, what would be the result?"

My point was that the impairment suggested in ME energy research is at the end of glycolysis with problems with pyruvate dehydrogenase that is needed to go on to the next stage in mitochondria. As far as I know there is no suggestion of impairment of glycolysis itself. It's what happens after glycolysis that is the problem.

[Added edit: If there's surplus pyruvate that can't be used in the mito, I think it's converted to lactic acid or lactate, not sure which, and the liver converts that either back to glucose or to glycogen or to fat.]

But I'll shut up now, as this needs someone more expert than me to answer your question.

I tried googling glycolytic impairment and found this which as far as I know is nothing to do with what happens in ME:
Glycolytic Pathway Defects

 

[Andy]

A pwME will put on more fat if eating 5kg of cake a week than someone who doesn't have ME, even with exactly the same activity levels?

But would we? My n=1 is that I was underweight for many years without limiting my calories in anyway, and in situations where I've met other pwME, I haven't seen many examples of those who I would describe as excessively fat. Now that is still a small sample set, and there will no doubt be a wide variation, but I'm not convinced there is any evidence of above avergae excessive weight in patients, especially considering our reduced activity levels.

 

[Wonko]

As far as I know the body only has two methods of handling excess and unused glucose.

It can either be excreted, or ut can be absorbed/converted into fat.

A possible hypothesis as to why some people get fat and some don't, or even get thinner, in the situation where glucose isn't being used correctly is that some oeoples kidneys have different thresholds for treating it as a txon and excreting it.

Is this threshold was, say, at the higher end of normal blood glucose levels then they would never have symptoms, other than the obvious, and never be tested or diagnosed for diabetes.

Just a hypothesis.

 

[Trish]

But would we? My n=1 is that I was underweight for many years without limiting my calories in anyway, and in situations where I've met other pwME, I haven't seen many examples of those who I would describe as excessively fat. Now that is still a small sample set, and there will no doubt be a wide variation, but I'm not convinced there is any evidence of above avergae excessive weight in patients, especially considering our reduced activity levels.

We have a thread on the forum where people discuss strategies for losing weight, so there are some people with ME who put on weight. Others find it hard to keep weight on because of low appetite, nausea, food intolerances etc.

As to the question of whether too much glucose circulating in the bloodstream puts on weight, the answer would appear to be the opposite. People with uncontrolled diabetes tend to lose weight:
https://www.diabetes.co.uk/symptoms...insufficient,reduction in overall body weight.

DIABETES AND SUDDEN WEIGHT LOSS
In people with diabetes, insufficient insulin prevents the body from getting glucose from the blood into the body’s cells to use as energy.

When this occurs, the body starts burning fat and muscle for energy, causing a reduction in overall body weight.

 

[Mij]

Adding muscle to your body burns fat because, well, muscle needs energy to survive.

My muscle mass has decreased quite a bit in the last 5 years, but I'm still not gaining pounds, it's just that my body weighs less because I have less muscle. Muscle is heavier than fat.

 

[Mithriel]

As a complete non expert who has read a lot I think all this is complicated by the individual's biochemistry. A very large study of the lean offspring of type 2 diabetics found that they had different way of processing fats and glucose. This matches the fact that diabetes is a particular problem in so called marginal areas where food was not always available. It is called a "thrifty genome". The implication is that being obese may be as much a product of this genome in a world of plenty as that diabetes is caused by being obese.

My husband's wider family are thin to very thin yet eat just as much as anyone else. If my husband misses a meal he stops being hungry. We think his liver is very good at releasing sugar whereas this does not happen with my relations.

Similarly, some people eat too much with depression whereas others stop eating.

Add to this that the control of blood sugar levels is controlled by the same mechanism of as temperature and things that don't work in ME and the fact we work on adrenalin a lot of the time which causes sugar cravings, it will take a supercomputer to work out what we should eat.

For myself, I need carbohydrates to function. I eat a fairly healthy diet and only have sugary things when I am hypoglycaemic but I have put on weight over the years.

In the early undiagnosed days, I was quite ill but forced to carry on. I was also very poor and missed a lot of meals but the weight kept piling up. Over the years I have noticed that if I do too much I put on weight so who knows what is going on.

 

[Mij]

My sister has Hashimoto and craves carbs and sweets. We can eat the same amounts of carbs/sweets and she will gain weight, but I won't. She is also quite active.

 

[Fizzlou]

https://www.healthrising.org/blog/2...gregor-metabolism-chronic-fatigue-glycolysis/

Hypermetabolism
A section on 3 different glucose responses (n=777) seen in pwME. Implication that Creatinine being used as fuel substitute hence low urea and creatinine values seen in blood panels. Similar effects seen in sepsis and burns patients.
Creatine anecdotally cited by some pwME as a PEM buster.
High incidence of diabetes and insulin sensitivity/resistance I've read somewhere?
I struggle to tolerate much glucose and experience what I assume is hyperglycemic rebound at night. Keto resolved this but I'm concerned about keto long term so I'm back to normalish diet. Lowish carbs, I.F, plenty of protein and veg and considering BCAA.

 

[Midnattsol]

We have a thread on the forum where people discuss strategies for losing weight, so there are some people with ME who put on weight. Others find it hard to keep weight on because of low appetite, nausea, food intolerances etc.

As to the question of whether too much glucose circulating in the bloodstream puts on weight, the answer would appear to be the opposite. People with uncontrolled diabetes tend to lose weight:
https://www.diabetes.co.uk/symptoms/unexplained-weight-loss.html#:~:text=In people with diabetes, insufficient,reduction in overall body weight.

In this case the weight loss is not due to excess glucose, but due to the cause of excess glucose. Cells need insulin for glucose uptake, when they become insulin-resistant* glucose stays in the blood (and some will be secreted in urine). Since the cells are not getting glucose to turn into ATP, they have to use fat or protein. PwME don't seem to develop this. Though, increased glucose can also be a sign of metabolic stress, it can occur in sepsis or after surgery.

If pwME turn lactate back into glucose for another round of glycolysis, that's a net "cost" of 4 ATP. Building glucose from lactate takes 6 ATP, you only get 2 from glycolysis (Cori cycle). Rather inefficient for long-term energy demand.

@Mij Same, I've lost kg, but it (thankfully) does not look like it except obviously my muscles aren't as defined as they were.

@Fizzlou Out of interest, if you're concerned over keto how did you land on I.F.? (I can't do either)

EDIT: *Or there is a lack of insulin (which happens in type 1 diabetes, while insulin-resistance is what happens in type 2 diabetes)

 

[Amw66]

In this case the weight loss is not due to excess glucose, but due to the cause of excess glucose. Cells need insulin for glucose uptake, when they become insulin-resistant glucose stays in the blood (and some will be secreted in urine). Since the cells are not getting glucose to turn into ATP, they have to use fat or protein. PwME don't seem to develop this. Though, increased glucose can also be a sign of metabolic stress.

If pwME turn lactate back into glucose for another round of glycolysis, that's a net "cost" of 4 ATP. Building glucose from lactate takes 6 ATP, you only get 2 from glycolysis (Cori cycle). Rather inefficient for long-term energy demand.

@Mij Same, I've lost kg, but it (thankfully) does not look like it except obviously my muscles aren't as defined as they were.

@Fizzlou Out of interest, if you're concerned over keto how did you land on I.F.? (I can't do either)

would insulin resistance not also affect leptin and grehlin signalling and thus the hunger response- body has lost calibration of satiety?

 

[Wonko]

would insulin resistance not also affect leptin and grehlin signalling and thus the hunger response- body has lost calibration of satiety?

Seems so.

(Not a medical opinion merely a personal one)

 

[Midnattsol]

would insulin resistance not also affect leptin and grehlin signalling and thus the hunger response- body has lost calibration of satiety?

These systems are very interconnected, yes, and leptin and ghrelin can also affect insulin.

 

[Fizzlou]

Out of interest, if you're concerned over keto how did you land on I.F.? (I can't do either)

After 6 months of Keto I experienced some benefit but not enough. I know children with epilepsy can tolerate this for quite some time and the benefits are profound. A lot of suggestion in scientific community that there are long term risks but quite honestly it's so poorly researched I can't be sure.
I slept better, improved a little but the inconvenience (energywise) of catering for family and myself was draining in itself. After stopping I didn't deteriorate other than the sleep. I think the benefit of keto for me was down to cutting out glucose and gluten. If that's it I can do that in less drastic ways.
In the past I have IF and this for me provides the single biggest boost. I find eating, generally makes me feel worse. Even on keto some food triggered symptoms. By narrowing my eating window I personally cope better.

 

[JES]

But would we? My n=1 is that I was underweight for many years without limiting my calories in anyway, and in situations where I've met other pwME, I haven't seen many examples of those who I would describe as excessively fat. Now that is still a small sample set, and there will no doubt be a wide variation, but I'm not convinced there is any evidence of above avergae excessive weight in patients, especially considering our reduced activity levels.

I think there are people in both camps as well, I had problems keeping weight and building muscle all my life and still in my 30's the BMI is on the low side without much activity. I think it does possibly tie with certain hypotheses of ME/CFS, one being that ME/CFS is kind of a hypometabolic or starvation type of response on the cellular level. In colloquial language people often tie a fast metabolism to losing weight and a low metabolism with the opposite, but I think it's not as simple in reality. It may be that we have metabolic issues making it difficult to process the energy in our food, but still some of us don't store it as extra fat, so the end result would be problems building up muscle and weight.